Process for the preparation of 17-lower alkoxy-4alpha, 8, 14-trimethyl-18-nor-5alpha, 8alpha, 9beta, 14beta-androsta-12, 16-diene-3, 11-dione



United States Patent PROCESS FOR THE PREPARATION OF 17-LOWER ALKOXY 404,8,14 TRIMETHYL 18 NOR 5oz, Sap 9,14 8-ANDROSTA-12,16-DIENE-3,1I-DIONE Imre Bacso, Somerset, and Patrick A. Diassi, Westfield, N.J., assignors to E. R. Squibb & Sons, Inc., New York, N.Y., a corporation of Delaware No Drawing. Continuation-impart of application Ser. No. 486,213, Sept. 9, 1965. This application May 3, 1967, Ser. No. 635,672

1 Claim. (Cl. 260397.45)

ABSTRACT OF THE DISCLOSURE This invention relates to 17-alkoXy-4a,8,14-trimethy1- 18 nor 5a,8o,9,8,13a,14{3 androstane 3,11,16,17- tetrone. Compounds falling within this invention possess anti-androgenic activity.

This is a continuation-in-part application of US. application, Ser. No. 486,213, filed Sept. 9, 1965, now Pat. No. 3,347,879.

This invention relates to and has as its object the provision of new physiologically active steroids, processes :for their preparation and novel intermediates useful in said preparation.

More particularly, this invention relates to the production of 17-a1koxy-4a,8,14-trimethyl-18-nor-5a,8u,9[i,14[3- androsta-IZ,16-diene-3,1l-dione.

The compound of this invention, in additionto being useful as an intermediate in further chemical synthesis of steroids has also been found to possess certain physiological activity. This compound possesses anti-androgenic activity, i.e., it inhibits the action of androgens and can be utilized in the treatment of such conditions as hyperandrogenic acne. The compound of this invention may be administered parentera'lly or orally, the dosage and/or concentration adjusted for the relative potency of the particular compound employed. It is preferred to administer the compounds of this invention in individual doses 3,3 91,171 Patented July 2, 1968 of from 0.025 to 1.0 mg/kg. of body Weight, but higher doses up to about 2.0 -mg./ kg. may be effective for those less potent compositions.

The compound of this invention may be prepared by the processes of this invention beginning with a cornpound having the formula wherein Ac is acyl as the starting material.

The preferred acyl radicals are those of hydrocarbon carboxylic acids of less than twelve carbon atoms, as exemplified by the lower alkanoic acids (e.g., acetic, propionic, butyric and tert-pentanoic acid), the lower alkenoic acids, the monocyclic aryl car-boxylic acids (e.g., benzoic and toluic acid), the monocyclic aryl lower alkanoic acids (e.g., phenacetic and fi-phenylpropionic acid), the cycloalkane carboxylic acids and the cycloalkene carboxylic acids.

It has been surprisingly found that when this starting material is hydrolyzed under mild conditions, for example, reacting it With perch loric acid and an alcohol such as methanol, ethanol, n-propan'ol, isopropanol and butanol at room temperature, a mixture of lfifl-hydroxy- 4a,8,l4 -trirnethy1- 18 nor 5u,8oc,9/i,13a,14fl androsta- 3,11,17-trione and a 17-alkoxy-4a,8,14-trimethyl-18-nor- 5a,8a,9fi,145 adrosta 12,16 diene 3,11 dione are LfOl'lIl'lGd. Oxidation of 16,8-hydr0Xy-4a,8,14-trirnethyl-18- nor-5a,8a,9 3,13a,14B-androsta-3,11,17-trione will yield 4oc,8,14 trimethyl 18 nor 5a,8ct,9,8,13u,14[3 androstane-3,11,16,17-tetrone and the tautomeric forms thereof. The reactions of this invention are as follows:

Example 1.16fl-hydroxy-4u,8,14-trimethyl-18 nor-a,

8a,9/3,13a,14,8 androsta 3,11,17-trione and 17 methoxy 4a,8,14,-trimethy1 18-nor 5a,8a,9;8,14,B-androsta-12,16-.diene-3,11-dione To a suspension of 1.0 g. of 16fi-acetoxy-4a,8,14-trimethyl-18-nor-5a,8ot,9fl,l3a,l4fi androsta 3,11,17 trione in 100 ml. of methanol 2.4 ml. of perchloric acid (70%) are added and the mixture stirred vigorously under helium for sixteen hours. The resulting solution is carefully diluted with water and the crystals which separate are filtered, washed with water and dried to give 140 mg. of 17 methoxy 40,8,l4-trimethyl-18-nor-5a,8a,9,B,145- androsta-12,16-diene 3,11 dione having a melting point about 175-177 C. [04 83 (chloroform),

A 230 m (6, 3,100), 304 my (6, 16,900), A232 5.88,

max.

Nuinl M...

8.82, (s, CH 8.92, (d, J=6 c.p.s., 4oz=CH 8.93 (s, CH

Analysis.-Calcd for C H O (346.45): C, 72.80; H, 8.73. Found: C, 72.69; H, 8.78. Example 2.-4a,8,14 trimethyl-l8-nor-5a,8ot,9fl,l3a,14,B- androstane-3,11,16,17-tetrone To a solution of 30 mg. of 16fl-hydroxy-40t,8,14-trimethyl-18 nor 504,806,913,13a,l4p-androsta-3,11,17-trione in 2.0 ml. of reagent grade acetone 1.0 ml. of an acetone-water solution (9:1, v.:v.) containing 10 mg. of chromic anhydride and 16 mg. of sulfuric acid per milliliter ih added dropwise with stirring. After five minutes the excess oxidizing agent is decomposed by adding a few drops of methanol and the mixture is diluted with water and extracted with chloroform. The chloroform is washed with water and evaporated under reduced pressure. Crystallization of the residue from acetone-hexane gives 17 mg. of 4a,8,14-trimethyl 18 I1OI-5oz,80z,9fi,l3oz,14,3- androstane-3,11,16,17-tetrone having a melting point about 228230 C.,

max.

While there have been described various embodiments of the invention, the compositions and methods described are not intended to be understood as limiting the scope of the invention, as it is realized that changes therein are possible and it is further intended that each element recited in any of the following claims is to be understood as referring to all equivalent elements for accomplishing substantially the same results in substantially the same or equivalent manner, it covering the invention broadly in whatever form its principle may be utilized.

What is claimed is:

1. A process for the preparation of 17-lower alkoxy-4a, 8,14-trimethyl-18-nor 5x,8a,9}8,14B androsta-12,l6-diene-3,11-dione which comprises reacting a compound having the formula ll O I QHa I OH;

3,274,219 9/1966 Krakower 260397.45

ELBERT L. ROBERTS, Primary Examiner. 

